Teixobactin And iChip Promise Hope Against Antibiotic Resistance

Teixobactin is the first new class of antibiotic announced in decades. That news and even more importantly, the elegant way it was discovered, are the most exciting news I’ve seen in some time.

Antibiotic development has stagnated as pharmaceutical companies have instead turned their attention to the far more profitable ventures of drugs for chronic diseases, like diabetes or heart disease. Antibiotics had been relegated to the role of the unwanted stepchild, it seemed.

Yet as antibiotics have been overused by healthcare workers (often at the demand of patients), sold over-the-counter in many countries, and wasted by agricultural misuse, we have seen their efficacy diminish.

About 99% of bacteria can’t be grown under our current lab⁠ techniques, according to Drs. Kim Lewis and Slava Epstein, of Northeastern University in Boston. Working with the National Institutes of Health and the German government, they have developed a remarkably clever new technique, which they call iChip, now licensed to NovoBiotic Pharmaceuticals. Soil is greatly diluted. Using a lattice of tiny wells holding individual bacteria within agar, the iChip is covered with a permeable membrane, and replaced into the original soil. Using this technique, Lewis’s team has been able to screen 10,000 bacteria, previously unculturable, discovering a new bacteria, Eleftheria terrae, which showed good activity against S. aureus, and 25 new compounds. Among them is Teixobactin, the most promising one to date. As Ed Yong⁠ puts it, "Teixobactin is a fish; the iChip is the rod. Having the rod guarantees that we’ll get more fish — and we desperately need more."

iChip in the field - Slava Epstein/Northeastern University

Why care?

Teixobactin is exciting for several reasons. First, is the novel technique by which it was discovered. The explanation in Nature for how the mechanism of action was found was intriguing as well, and relied on “in silico,” or computer modeling to help work out. This compound is promising as an antibiotic for several reasons. First, it is a new cell wall inhibitor type of antibiotic, meaning it blocks bacteria from being able to reproduce. It binds to lipid II, and is different in its action than other glycopeptide drugs, like vancomycin or dalbavancin.

Teixobactin shows great activity against some of the problem Gram positive superbugs I deal with regularly—MRSA, enterococci, and C. diff—and has activity against tuberculosis and B. anthraces. Importantly, the drug is bactericidal vs VISA (Vancomycin Intermediate S. aureus)—meaning it will kill this resistant bacteria, a scourge of hospitals.

Unfortunately, Teixobactin does not have activity against Gram negative pathogens—such as Carbapenem-resistant Enterobacteraceae (CRE) or NDM bugs—which are a growing threat to patients.

In mouse studies, Teixobactin showed 100% efficacy against MRSA sepsis and in thigh infections, and was very active against S. pneumoniae in lungs. No toxicity was seen against the mammal cells tested, no hemolytic activity, and it did not bind DNA, so the researchers are optimistic about its likely toxicity.

First, there is a very, very long path from drug discovery and mouse trials to the market. This path often takes 10+ years; the NovoBiotic researchers are hoping for 5. Importantly, mice are not people, and we have no idea what toxicities might be seen in people. In fact, only 8% of compounds that pass into the animal testing phase ever make it to market⁠. In addition to the toxicity, efficacy has to be shown—this will be particularly difficult to do with device infections.

The researchers are too glowingly optimistic about the likelihood of resistance emerging, I believe. In fact, the compound is being touted as “resistant to resistance” based on lab testing. Bacteria are always smarter than the people who develop and use them. While it may have taken 30+ years for Vancomycin resistance to develop, in part that is likely because we didn’t use that much of it until the last decade. Now we regularly see VISA organisms, with reduced susceptibility to Vancomycin and occasionally a totally Vanc resistant isolate.

For Vanc resistance, we now often turn to Daptomycin. Discovered in soil from Mt. Ararat, Turkey, Cubist got FDA approval for Daptomycin in 2003.⁠ In contrast to the slow resistance with Vancomycin, a case of Daptomycin resistant S. aureus bacteremia⁠ (blood stream infection) was reported in 2005. This past summer, I saw Dapto resistance emerge, similarly in patients with inadequately drained foci of infection.

My biggest concern, should Teixobactin make it to market, is that it will be squandered as every other good new antibiotic has been, and so resistance will rapidly emerge as the drug is overused. I have particularly been disappointed to see this with the other novel antibiotics developed during my career—Linezolid (Pfizer) and Daptomycin. I see both marketed irresponsibly (including promoting use to Social Service case workers) because they are convenient to use. Medicare has not been willing to pay for home IV antibiotics, so many of us use Daptomycin, which can be given once-daily in an outpatient clinic, so that our patients won’t have to go to a nursing home to receive antibiotics. As a result, we’re creating bacteria resistant to one of our few remaining effective antibiotics. Similarly, Linezolid is wasted for convenience, since it can be given orally; it has also been promoted for inappropriate uses, as treating colonization in wounds or in nursing home patients, rather than infection.

iChip is a very exciting development, allowing screening of previously unculturable bacteria for useful compounds. Teixobactin has promise because of its novel mechanism of action and its relative resistance to the emergence of resistance—in the lab. It has a long way to be more than a wish and a promise. If we don’t put strict controls on its use and treat it as a treasure, it won’t last long.

I always let my children grub in the dirt, believing it to be good for their immunity. Now we have new evidence of the wonders in dirt—at least in Maine, the source of Teixobactin.

I am an Infectious Disease specialist, experienced in conducting clinical research and the author of Conducting Clinical Research, the essential guide to the topic. I survived 25 years in solo practice in rural Cumberland, Maryland, and now work part time as an Infectious Di...